Implant made of a biodegradable magnesium alloy

ABSTRACT

A vascular implant made in total or in parts of a biodegradable magnesium alloy consisting of Y: 2.0-6.0% by weight, Nd: 1.5-4.5% by weight, Gd: 0-4.0% by weight, Dy: 0-4.0% by weight, Er: 0-4.0% by weight, Zr: 0.1-1.0% by weight, Li: 0-0.2% by weight, Al: 0-0.3% by weight, under the condition that a) a total content of Er, Gd and Dy is in the range of 0.82-4.0% by weight and b) a total content of Nd, Er, Gd and Dy is in the range of 2.98-8.5% by weight, the balance being magnesium and incidental impurities up to a total of 0.3% by weight.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a continuation of U.S. patent application Ser. No. 12/566,312,filed Sep. 24, 2009, which claims benefit of priority to European patentapplication EP 08165463.4, filed on Sep. 30, 2008; the contents of whichare herein incorporated by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to implants made of a biodegradablemagnesium alloy.

BACKGROUND OF THE INVENTION

Medical implants for greatly varying uses are known in the art. A sharedgoal in the implementation of modern medical implants is highbiocompatibility, i.e., a high degree of tissue compatibility of themedical product inserted into the body. Frequently, only a temporarypresence of the implant in the body is necessary to fulfil the medicalpurpose. Implants made of materials which do not degrade in the body areto be removed again, because rejection reactions of the body may occurin long term even with highly biocompatible permanent materials.

One approach for avoiding additional surgical intervention is to formthe implant entirely or in major parts from a biodegradable (orbiocorrodible) material. The term biodegradation as used herewith isunderstood as the sum of microbial procedures or processes solely causedby the presence of bodily media, which result in a gradual degradationof the structure comprising the material. At a specific time, theimplant, or at least the part of the implant which comprises thebiodegradable material, loses its mechanical integrity. The degradationproducts are mainly resorbed by the body, although small residues beingin general tolerable.

Biodegradable materials have been developed, inter alia, on the basis ofpolymers of synthetic nature or natural origin. Because of the materialproperties, but particularly also because of the degradation products ofthe synthetic polymers, the use of biodegradable polymers is stillsignificantly limited. Thus, for example, orthopedic implants mustfrequently withstand high mechanical strains and vascular implants,e.g., stents, must meet very special requirements for modulus ofelasticity, brittleness, and moldability depending on their design.

One promising attempted achievement provides the use of biodegradablemetal alloys. For example, it is suggested in German Patent ApplicationNo. 197 31 021 A1 to form medical implants from a metallic materialwhose main component is to be selected from the group of alkali metals,alkaline earth metals, iron, zinc, and aluminium. Alloys based onmagnesium, iron, and zinc are described as especially suitable.Secondary components of the alloys may be manganese, cobalt, nickel,chromium, copper, cadmium, lead, tin, thorium, zirconium, silver, gold,palladium, platinum, silicon, calcium, lithium, aluminium, zinc, andiron.

The use of a biodegradable magnesium alloy having a proportion ofmagnesium greater than 90% by weight, yttrium 3.7-5.5% by weight, rareearth metals 1.5-4.4% by weight, and the remainder less than 1% byweight is known from European Patent 1 419 793 B1. The materialdisclosed therein is in particular suitable for producing stents.

Another intravascular implant is described in European PatentApplication 1 842 507 A1, wherein the implant is made of a magnesiumalloy including gadolinium and the magnesium alloy is being free ofyttrium.

Stents made of a biodegradable magnesium alloy are already in clinicaltrails. In particular, the yttrium (W) and rare earth elements (E)containing magnesium alloy ELEKTRON WE43 (U.S. Pat. No. 4,401,621) ofMagnesium Elektron, UK, has been investigated, wherein a content ofyttrium is about 4% by weight and a content of rare earth metals (RE) isabout 3% by weight. The following abbreviations are often used: RE=rareearth elements, LRE=light rare earth elements (La—Pm) and HRE=heavy rareearth elements (Sm—Lu). However, it was found that the alloys respond tothermo-mechanical treatments. Although these types of WE alloysoriginally were designed for high temperature applications where highcreep strength was required, it was now found that dramatic changes inthe microstructure occurred during processing with repetitivedeformation and heat treatment cycles. These changes in themicrostructure are responsible for high scrap rates during productionand inhomogeneous properties of seamless tubes and therefore in thefinal product. As a consequence, mechanical properties are affectedharmful. Especially, the tensile properties of drawn tubes in theprocess of manufacturing stents are deteriorated and fractures appearduring processing. In addition, a large scatter of the mechanicalproperties especially the elongation at fracture (early fractures of thetubes below yield strength during tensile testing) was found in thefinal tube. Finally, the in vivo degradation of the stent is too fastand too inhomogeneous and therefore the biocompatibility may be worstedby inflammation process caused by a tissue overload of the degradationproducts.

The use of mixtures of light rare earth elements (LRE; La, Ce, Pr, Nd)and heavy rare earth metals (HRE; elements of the periodic table: Sm,Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu) in commercially availablemagnesium alloys such as WE43 rather than pure alloying elements reducedthe costs and it has been demonstrated that the formation of additionalprecipitates of these elements beside the main precipitates based on Yand Nd further enhance the high temperature strength of the material[King et al, 59th Annual World Magnesium Conference, 2005, p. 15ff]. Itcould therefore be postulated the HRE containing precipitates are morestable against growth at higher temperatures because of thesignificantly slower diffusion rate of these elements compared to Y andNd. Therefore they contribute substantially to the high temperaturestrength of WE alloys (particle hardening effect).

However, it now has been found that these HRE precipitates are causingproblems when the material is used in biomedical applications, such asvascular implants (e.g. stents) or in orthopaedic implants. The HREintermetallic particles adversely affect the thermo-mechanicalprocessability of alloys. For example, manufacturing vascular prostheseslike stents made of metallic materials usually starts from drawnseamless tubes made of the material. The production of such seamlesstubes is usually an alternating process of cold deformation by drawingand subsequent thermal treatments to restore the deformability andductility, respectively. During the mechanical deformation stepsintermetallic particles cause problems because they usually havesignificant higher hardness than the surrounding matrix. This leads tocrack formation in the vicinity of the particles and therefore todefects in the (semi-finished) parts which reduces their usability interms of further processing by drawing and also as final parts forproduction of stents.

Intermetallic precipitates also adversely affect the recrystallizationbehaviour during heat treatments for restoring the plasticity.Impurities are known to affect grain boundary mobility strongly,depending on segregation and mobility. Further, not only the volumefailures (precipitates) in the microstructure but also point failures(foreign atoms=all alloying elements) and especially RE atoms contributeto this adverse effect.

Surprisingly it now has been found that precipitation still happens tooccur although the temperature regime is high enough that one wouldexpect dissolution of all existing particles. This indicates thatintermetallic phases predominantly formed with LRE cannot be dissolvedduring usual recrystallization heat treatment (300 to 525° C.) of thespecific alloys. As a consequence, the ductility for further deformationprocesses or service cannot be restored sufficiently.

SUMMARY OF THE INVENTION

An aim of this invention is to overcome or to at least lower one or moreof the above mentioned problems. There is a demand for a biodegradableMg alloy having improved processability and, if applicable, improvedmechanical properties of the material, such as strength, ductility andstrain hardening. In particular, in case of that the implant is a stenta scaffolding strength of the final device as well as the tube drawingproperties of the material should be improved.

A further aspect of the invention may be to enhance the corrosionresistance of the material, more specifically, to slow the degradation,to fasten the formation of a protective conversion layer, and to lessenthe hydrogen evolution. In case of a stent, enhancing the corrosionresistance will lengthen the time wherein the implant can providesufficient scaffolding ability in vivo.

Another aspect of the invention may be to enhance the biocompatibilityof the material by avoiding toxic components in the alloy or thecorrosion products.

One or more of the above mentioned aspects can be achieved by theimplant of the present invention. The inventive implant is made in totalor in parts of a biodegradable magnesium alloy consisting of:

-   -   Y: 2.0-6.0% by weight    -   Nd: 1.5-4.5% by weight    -   Gd: 0-4.0% by weight    -   Dy: 0-4.0% by weight    -   Er: 0-4.0% by weight    -   Zr: 0.1-1.0% by weight    -   Li: 0-0.2% by weight    -   Al: 0-0.3% by weight    -   under the condition that        -   a) a total content of Er, Gd and Dy is in the range of            0.5-4.0% by weight and        -   b) a total content of Nd, Er, Gd and Dy is in the range of            2.0-5.5% by weight,    -   the balance being magnesium and incidental impurities up to a        total of 0.3% by weight.

The use of the inventive Mg—Y—(Nd—)HRE-Zr alloy for manufacturing animplant causes an improvement in processability, an increase incorrosion resistance and biocompatibility compared to conventionalmagnesium alloys, especially WE alloys such as WE43 or WE54.

Recrystallization, i.e. the ability to form new unstrained grains, isbeneficial in restoring ductility to material, which has been strained,for example by extrusion, rolling and drawing. Recrystallization allowsmaterial to be restrained to achieve further deformation.Recrystallization is often achieved by heating the alloy betweenprocessing steps. If recrystallization temperature can be lowered, theextent of elevated temperature annealing steps can be reduced, andforming of the material can be improved.

It is well recognised that one of the factors which affectsrecrystallization is the purity of the material; an example being theeffect of copper content in aluminium alloys compared with zone refinedaluminium [Vandermeer et al., Proc. Symposium on the recovery anrecrystallization of metals, New York, TMS AIME, 1962, p. 211]. It maybe expected therefore, that improving the purity of Mg—Y—(Nd—)HRE-Zralloys, by for example, reducing low levels of LRE and HRE would reducethe recrystallisation temperature. However, for magnesium alloyscontaining RE elements, it has been reported that RE elements increasethe recrystallisation temperature. This fact may be related to increasedactivation energy of recrystallisation. Furthermore, it was observedthat the recrystallisation temperature is in general increased incorrespondence with the solubility of the RE elements in magnesium, i.e.the more soluble the RE, the higher is the recrystallisation temperature[Rokhlin, Magnesium Alloys containing Rare Earth Metals, 2003, p.143ff].

Lorimer et al., Materials Science Forum, Vols. 488 to 489, 2005, p. 99ff, propose that in WE43 alloy, recrystallisation can occur at secondphase particles and Particle Simulated Nucleation (PSN) is a mechanismof recrystallisation.

From the above it can be assumed that the direction of teaching forMg—Y—(Nd—)HRE-Zr type alloys is that generation of RE particles could bebeneficial to recrystallisation, but also that increasing RE content(particularly soluble RE) would increase recrystallisation temperature,except for small amounts, where no difference in recrystallisation wouldbe expected.

The presence of particles in Mg—Y—(Nd—)HRE—Zr can be related to any ofthe constituent elements. Of particular interest to this invention, arethe HRE and LRE constituents. WE43 type alloys typically contain 1% RE,which can consist of HRE elements such Sm Eu, Gd, Dy, Er, Yb and LREelements such as La, Ce and Pr. For example, WE43 manufactured byMagnesium Elektron is composed of Y 3.7-4.3%, RE 2.4-4.4%, Zr 0.4% minand balance magnesium, wherein RE stands for Nd 2.0-2.5% and theremainder being RE elements. Thus, LRE and HRE are present in Mg—Y—RE—Zralloys of the art. Y and Nd are the elements, which improve strength byprecipitation hardening. This relies on the fact that these alloyconstituents are in a state of supersaturation and can subsequently bebrought out of solution in a controlled manner during ageing (typicallyat temperatures in the range 200 to 250° C.). The precipitates desiredfor strength are small in size and could not be readily resolved byoptical microscopy. Additional precipitates are also generated which arecoarse and readily observed optically as particles. These are usuallyrich in Nd. These coarse particles are brittle, and may be expected toreduce formability and ductility of the material.

The solubility of RE in magnesium varies considerably; see Table 1.

TABLE 1 Solid solubility of various LRE and HRE in magnesium AtomicSolid solubility at various temperatures (weight %) number Element 200°C. 400° C. 500° C. 68 Er 16 23 28 66 Dy 10 17.8 22.5 64 Gd 3.8 11.5 19.270 Yb 2.5 4.8 8 62 Sm 0.4 1.8 4.3 58 Ce 0.04 0.08 0.26 59 Pr 0.01 0.20.6 60 Nd 0.08 0.7 2.2 57 La — 0.01 0.03

From the above, it may be expected to one skilled in the art, that thevolume of coarse particles present would be primarily related to the Ndcontent, due to the low solid solubility of this element.

It now has been discovered however, that by restricting the remainingRE—without changing the Nd or the overall RE content compared toconventional WE43 alloys—to either Er, Gd or Dy of the HRE group or amixture of these elements, that the volume of coarse Nd rich particlesis significantly reduced. This is unexpected, particularly when oneconsiders that the solubility of other HRE elements such as Yb and Smwould be expected to be retained in solution and not contribute tocoarse particles. Only La is insoluble in the range of compositionsexplored even though the quantity is very small. As such removal ofthese LRE and HRE elements and replacement with Gd/Dy/Er would not beexpected to make a material difference to the quantity of coarseparticles.

It has been found that the recrystallization behaviour during a heattreatment of the alloy is improved, i.e. heat treatment for completerecrystallization is possible at lower temperature or at shorter timeswith less probability for excessive grain growth. The later effect ingeneral leads to microstructures having a larger grain size which isdetrimental to the mechanical properties. Use of the inventive magnesiumalloy has thus an advantage in terms of processability, is moreeconomical and improves the mechanical properties of the alloy.

It could be demonstrated that the magnesium alloy of the inventionincludes significantly less precipitates and has a larger grain sizeafter extrusion compared to conventional WE alloys. It is assumed thatthe beneficial effects in processability contribute to the low contentof elements forming intermetallic precipitates as well as pointfailures.

Examination of the microstructure of the inventive magnesium alloy andconventional WE43 revealed that after several deformation steps andsubsequent intermediate heat treatments there were significant less andsmaller precipitates in the inventive magnesium alloy than in WE43processed in exactly the same way.

In other words, the selection of the type of RE and HRE, present inMg—Y—(Nd—)HRE—Zr alloy, has surprisingly led to an improvement in theformability characteristics. It is proposed, that this improvement isachieved by a reduction in hard particles (precipitated) and/or byreducing recrystallisation temperature.

It is well known, that general corrosion of magnesium alloys is affectedby contaminants such as iron, nickel, copper and cobalt. This is due tothe large difference in electrochemical potential between these elementsand magnesium. In corrosive environments, micro galvanic cells areproduced, which leads to corrosion. Addition of REs to magnesium hasbeen reported to have some effect on corrosion of binary alloys. Untilnow, there does not however appear to be clear teaching, upon the effectof changing small amounts (in the region of this patent application) ofRE/HRE on the corrosion performance of magnesium alloys. Surprisingly,it has been found that by selecting the RE/HRE content ofMg—Y—(Nd—)HRE—Zr, that corrosion performance was improved by a factor ofapproximately four. This occurred, without reducing the overall totalRE/HRE content of the alloys investigated. The reduction in particlesobserved in Mg—Y—(Nd—)HRE—Zr alloy by reducing the less favourableHRE/RE is more than would be expected from the amounts of detrimentalHRE/RE replaced by the more favourable ones.

Beside that an improvement of the corrosion resistance of the alloy inPBS (phosphate buffered saline) has been demonstrated. Samples made ofthe inventive alloy showed a slower degradation rate that samples madeof conventional WE43. These in vitro measurements under physiologicalconditions were confirmed by in vivo results from animal trails withmini pigs.

In summary, the benefit of lower recrystallisation temperature andreduced particles is an improvement in ductility, and improvedformability, during forming operations; thus scrap and processing timecan be reduced. In addition, the corrosion performance of the materialhas been improved. All of the above changes are achieved, without achange in the overall RE/HRE content of the alloy compared toconventional WE43 alloys and without detriment to mechanical strength ofthe material.

Preferably, the content of Y in the Mg—Y—(Nd—)HRE—Zr alloy is 3.5-4.5%by weight, most preferred 3.9-4.1% by weight. Keeping the content of Ywithin the ranges ensures that the consistency of properties, e.g.scatter during tensile testing, is maintained.

The content of Nd in the Mg—Y—Nd—HRE—Zr alloy is 1.5-4.5% by weight,preferably 1.5-3.0% by weight, more preferred 2.0-3.0% by weight, mostpreferred 2.0-2.5% by weight. When the content of Nd is at least 1.5% byweight, the strength of the alloy is increased. However, when thecontent of Nd is above 4.5% by weight, the ductility of the alloy isdeteriorated due to a limited solubility of Nd in Mg.

In addition, the content of Zr in the Mg—Y—(Nd—)HRE—Zr alloy ispreferably 0.1-0.7% by weight. For magnesium-zirconium alloys, zirconiumhas a significant benefit of reducing the grain size of magnesiumalloys, especially of the pre-extruded material, which improves theductility of the alloy.

It has further been shown that impurities of iron and nickel areeffectively controlled due to zirconium and aluminium combining withiron and nickel to form an insoluble compound. This compound isprecipitated in the melting crucible and settled prior to casting [Emleyet al., Principles of Magnesium Technology. Pergamon Press 1966, p.126ff; U.S. Pat. No. 3,869,281]. Thus Zr and Al contribute to improvedcorrosion/degradation resistance. To ensure these effects the content ofZr should be at least 0.1% by weight while the content of Al should beless than 0.3%. Preferably, the inventive magnesium alloy includes lessthan 0.2% by weight Al.

A total content of Er, Gd and Dy in the Mg—Y—(Nd—)HRE—Zr alloy ispreferably in the range of 0.5-1.5% by weight, more preferred 0.5-1.0%by weight.

A total content of Nd, Er, Gd and Dy in the alloy is preferably in therange of 2.0-3.5% by weight. Within this range, maintenance of ductilitycan be ensured.

Preferably, the inventive magnesium alloy includes Gd and Dy, especiallysolely Gd.

Preferably, the inventive magnesium alloy includes less than 0.02% byweight Li.

The total content of impurities in the alloy should be less than 0.3% byweight, more preferred less that 0.2% by weight. In particular, thefollowing maximum impurity levels should be preserved:

-   -   Ce, Yb, Sm, La, Zn, Fe, Si, Cu, Mn, Ag: 0.05% individually by        weight Ni: 0.003% by weight

The processing of the biodegradable magnesium alloys has a significanteffect on the processability and ductility of the material. Instructural terms it has been found that an improvement in processabilityand/or ductility becomes noticeable when the area percentage ofparticles in the alloy having an average particle size in the range of 1to 15 μm is less than 3%, and particularly less than 1.5%. Mostpreferred the area percentage of particles having an average sizegreater than 1 μm and less than 10 μm is less than 1.5%. Thesedetectable particles tend to be brittle.

For purposes of the present disclosure, alloys are referred to asbiodegradable in which degradation occurs in a physiologicalenvironment, which finally results in the entire implant or the part ofthe implant formed by the material losing its mechanical integrity.Artificial plasma, as has been previously described according to EN ISO10993-15:2000 for biodegradation assays (composition NaCl 6.8 g/l. CaCl₂0.2 g/l. KCl 0.4 g/l. MgSO₄ 0.1 g/l. NaHCO₃ 2.2 g/l. Na₂HPO₄ 0.126 g/l.NaH₂PO₄ 0.026 g/l), is used as a testing medium for testing thecorrosion behavior of an alloy coming into consideration. For thispurpose, a sample of the alloy to be assayed is stored in a closedsample container with a defined quantity of the testing medium at 37° C.At time intervals-tailored to the corrosion behaviour to be expected-ofa few hours up to multiple months, the sample is removed and examinedfor corrosion traces in a known way.

Implants are devices introduced into the body via a surgical method andcomprise fasteners for bones, such as screws, plates, or nails, surgicalsuture material, intestinal clamps, vascular clips, prostheses in thearea of the hard and soft tissue, and anchoring elements for electrodes,in particular, of pacemakers or defibrillators. The implant ispreferably a stent.

Stents of typical construction have filigree support structures made ofmetallic struts which are initially provided in an unexpanded state forintroduction into the body and are then widened into an expanded stateat the location of application.

Vascular implants, especially stents, are preferably to be designed inregard to the alloys used in such a way that a mechanical integrity ofthe implant is maintained for 2 through 20 weeks. Implants as anoccluder are preferably to be designed in regard to the biodegradable insuch a way that the mechanical integrity of the implant is maintainedfor 6 through 12 months. Orthopedic implants for osteosynthesis arepreferably to be designed in regard to the magnesium alloy in such a waythat the mechanical integrity of the implant is maintained for 6 through36 months.

BRIEF DESCRIPTION OF THE DRAWINGS

The present disclosure is explained in greater detail in the followingon the basis of exemplary embodiments and the associated drawings.

FIGS. 1A and 2A show microstructures of samples made of a conventionalWE alloy after extrusion at 450° C. and after tube drawing;

FIGS. 1B and 2B show microstructures of samples made of the inventivemagnesium alloy after extrusion at 450° C. and after tube drawing;

FIG. 3A is a graph demonstrating Mg release rates in PBS of samples madeof a conventional WE alloy or the inventive magnesium alloy;

FIG. 3B is a graph demonstrating the polarization resistance of samplesmade of a conventional WE alloy or the inventive magnesium alloy; and

FIG. 4 demonstrates the in vivo degradation of stents made of aconventional WE alloy or the inventive magnesium alloy after 2respectively 4 weeks after implantation.

DETAILED DESCRIPTION OF THE INVENTION

Several melts with different alloy compositions were melted and cast,extruded and were subject to different investigation with the emphasison the microstructure (grain size, size, fraction and composition ofprecipitates) and the respective thermo-mechanical properties (tensileproperties, recovery and recrystallization behaviour). In general, meltswere carried out according to the following casting technique:

Alloys were prepared, by melting in steel crucibles. The melt surfacewas protected by use of protective gas (CO₂/2% SF₆). Temperature wasraised to 760-800° C. before the molten alloy was stirred to homogenisethe melt chemistry. The molten alloy was then cast into a mould toachieve a billet of nominally 120 mm diameter and 300 mm length.

The billet was machined to nominally 75 mm diameter and 150-250 mmlength. The billet was homogenised, by heating to approximately 525° C.for 4-8 hours.

Extrusion was carried out on a hydraulic press. The product was roundbar section, with 3.2 mm to 25 mm, more typical 9.5 mm diameter.Following extrusion, approximately 300 mm of extrude, was discarded fromeach end of the extruded section. The remaining material was used forevaluation.

Table 2 summarises the chemical compositions, corrosion rates andtensile properties of exemplary extruded Mg—Y—Nd—HRE—Zr alloys. SF2894,SF4619 and SF4355 are comparative examples of commercially available WEalloys. Each time, two melts were produced to generate tensile data andfor metallography. The yield strength (YS; or yield point) of a materialis defined as the stress at which material strain changes from elasticdeformation to plastic deformation, causing it to deform permanently.UTS means Ultimate Tensile Strength defined as the maximum stress amaterial can withstand before break. Elongation stands for elongation atfracture.

As can be seen form the data of Table 2, the inventive changes in thecomposition of the alloys were not detrimental to tensile properties interms of strength, but in the case of ductility as measured byelongation, a noticeable improvement was observed where the HREcomponent of the alloys was rich in Gd/Dy/Er.

FIG. 1 shows microstructures of comparative sample SF2894 (FIG. 1A) andsample DF9083 (FIG. 1B) after extrusion at 450° C. For thismetallographic examination of the as extruded condition the materials,SF2894 and DF9083, were melted, cast, homogenized, cut to billets andextruded to bars. Then samples were cut, embedded in epoxy resin,ground, polished to a mirror like finish and etched according tostandard metallographic techniques [G Petzow, Metallographisches,keramographisches and plastographisches Ätzen, Borntraeger 2006].

FIG. 2 shows microstructures of comparative sample SF2894 (FIG. 2A) andsample DF9083 (FIG. 2B) after extrusion and subsequent tube drawing. Forthe metallographic examination of drawn tubes the materials the extrudedbars from the previous section were deep hole drilled and cold drawn inseveral steps (5-20% deformation per step) with intermediate heattreatments (350° C. to 525° C. for 10 min to 48 h depending on degree ofdeformation and sample size) to the final tube size with a diameter of 2mm and a wall thickness of about 0.2 mm. Then samples preparation wasthe same as in the previous section.

As can be seen from FIGS. 1A and 1B, the inventive magnesium alloy hassignificantly less precipitates and a slightly larger grain size afterextrusion. The investigation further revealed in FIGS. 2A and 2B thatafter several deformation steps and the respective intermediate heattreatments there are significant less and smaller precipitates in sampleDF9083 and that the grain size of sample DF9083 is still slightly largerthan for comparative example SF2894 processed exactly the same way.

The investigation further revealed that the mechanical properties ofboth drawn tubes differ slightly in terms of strength (YS=160-175 MPa;UTS=240-260 MPa) but significantly in terms of scatter in the elongationat fracture (SF2894=10-20%; DF9083=18-23%). The fact that the inventivealloy reaches almost the same maximum elongation at fracture with acoarser microstructure also clearly indicates that even higherelongations at fracture are achieved by adjustment of the grain sizewith an appropriate recrystallization heat treatment.

In a preliminary test it could be demonstrated that the inventivemagnesium alloys are less sensitive to temperature variations. Inparticular, the range between uniform elongation and elongation atfracture is more uniform compared to conventional magnesium alloys. Theinventive alloys soften at a lower annealing temperature thanconventional alloys and thus ductility is maintained at a more uniformlevel.

Beside the improvement of the mechanical properties and through this theimprovement in processability, there was also found for the alloys ofthe present invention an improvement in the corrosion properties. Forcorrosion testing extruded bar samples were machined and tested in 5%NaCl salt fog environment for 7 days in accordance with ASTM B117.Corrosion product was removed using a boiling solution of 10% chromiumtrioxide solution. Weight loss of samples was determined and isexpressed in mpy (mils penetration per year). The tested alloys exhibita corrosion rate as measured according to ASTM B117 of less than 30 Mpy.Thus, it can be seen that there is an improvement in salt fog corrosionperformance compared to conventional biodegradable magnesium alloys.

Since it is known that different corrosion media lead to differentcorrosion behaviour the corrosion resistance of the materials were inaddition characterized by electrochemical impedance spectroscopy (EIS)and quantification of the Mg ion release in solutions (SBF and PBS,)simulating the actual implant environment. For EIS measurements samplesof the as extruded condition were used in a conventional three electrodeassembly (sample=working-, reference- and counter-electrode) and apotentiostat as described elsewhere.

The measurement of the complex resistance (polarization resistance) withelectrochemical impedance spectroscopy in SBF (Simulated Body Fluid)revealed significantly higher resistances of the inventive magnesiumalloy of sample DF9083 (bold symbols; see FIG. 3B) compared to theconventional magnesium alloy of sample SF4355 (plain symbols; FIG. 3B)indicating the higher corrosion resistance of the inventive extrudedmaterial.

Since it is also known that the thermo-mechanical history of materialsaffects the corrosion behaviour we also characterized the corrosionresistance of the materials by quantification of the Mg ion release ofactual fully processed stents in PBS.

The samples for the Mg ion release tests were manufactured from drilledsleeves of the as extruded material and from drawn tubes. The sleevesand tubes were laser beam cut to the shape of stents, electro-polished,crimped on balloon catheters, sterilized and expanded into hoses ofappropriate size where they were surrounded be flowing PBS. Samples fromthe test solution were taken a different time points and subject toquantitative Mg ion evaluation by means of a photometric proceduredescribed elsewhere.

The measurement of Mg release from actual implants (stents) in PBS(Phosphate Buffered Saline) clearly indicates that the dissolution ofmaterial produced from drawn material of the sample DF9083 (boldsymbols; see FIG. 3A) is reduced with respect to the dissolution ofstents produced from drawn tubes made of comparative sample SF4355(plain symbols; see FIG. 3A). It also clearly indicates materialproduced from as extruded DF9083 material (dashed line; FIG. 3A) withoutany further thermo-mechanical processing has a slower degradation ratethan material produced from drawn SF4355 tubes (plain symbols; see FIG.3A). It further indicates that material after severe (repetitive)thermo-mechanical processing, here tube drawing, (DF9232 drawn; boldsymbols; FIG. 3A) exhibits a slower degradation rate than materialproduced from extruded DF9232 material (dashed line; FIG. 3A) withoutany further thermo-mechanical processing.

As mentioned before the actual implant environment can hardly besimulated in vitro. Therefore the most reliable test regarding theproperties (biological, mechanical, corrosion) is the in vivo test inanimal studies.

The study objective was to test alloy DF9232 compared to SF4355 with aview to the impact on degradation speed and tissue reactions. This studywas a randomized, controlled animal study on 21 minipigs. It was aspiredto implant each animal with one stent in each of the three largecoronary arteries. 21 SF4355 and 42 DF9232 stents were implanted.Follow-up investigations were performed after 2 and 4 weeks. Afterexplantation the arteries were subjected to morphometrical andhistopathological examination.

The pig was selected as the test animal for this study because it is arecognized and proved animal model for stent implantations (R S.Schwartz “Drug Eluting Stents in Preclinical Studies”; Circulation, Vol.106, 2002, p. 1867-1873; A G. Touchard and R S. Schwartz “PreclinicalRestenosis Models: Challenges and Successes” Toxicologic Pathology, Vol.34, 2006, p. 11-18). The anatomy of the pig's coronary system is verysimilar to that of a human. Furthermore, the expected long-termbehaviour of a stent in a human can be assessed in a pig in acomparatively short period of time as all the factors of a vascularresponse occur five to six times faster in the pig.

The study protocol was approved by the animal protection authorities andthe animal commission. The protocol complies with the conditions andregulations of the “German Animal Protection Act (May 25, 1998)” andwith the guidelines of ISO 10993-2 (Biological Assessment of MedicalProducts Part 2: Animal Protection Regulations).

To evaluate the influence on the degradation speed the samples from themorphometric evaluation of vessel parameters were further investigatedwith respect to the ratio between remaining metallic material of thestent struts and the original strut size.

FIG. 4 demonstrates the in vivo degradation of stents made of theconventional material of sample SF4355 and the inventive magnesium alloyof sample DF9232, each after 2 respectively 4 weeks after implantation.It can be seen that the inventive magnesium alloy of sample DF9232exhibited significant less degradation indicated by the significantlower degradation score.

Table 3 sets out the estimated area and mean size data of particlesfound in a selection of alloys. The technique used was opticalmicroscopy using commercially available software to analyse particlearea and size by difference in colouration of particles. This techniquedoes not give an absolute value, but does give a good estimation whichwas compared with physical measurement of random particles. Table 3clearly illustrates a reduction in the number of detectable particles inthe alloys of this invention, and these particles are likely to bebrittle.

TABLE 3 Area of particles as Mean Diameter Melt Number percentage ofmatrix (%) (microns) SF2894 5.8 4.3 SF4619 3.5 2.6 DF9520 1.5 3 DF90810.1 0.8 DF9082 0 1 DF9548 1.1 1.2 DF9083 0.7 2.4 DF9545 0.5 1.2 DF95181.7 2.6 DF9547 5.3 2.4

TABLE 2 Chemical composition, corrosion rate and tensile properties ofextruded Mg—Y—Nd-HRE-Zr alloys Chemical Analysis [wt %] ID Y Nd Zr Gd DyEr Yb Sm La Ce Li SF2894 3.74 2.15 0.52 0.15 0.21 0.10 0.05 0.06 0.060.01 0.00 SF4619 3.90 2.20 0.56 0.28 0.30 0.09 0.03 0.03 0.00 0.00 0.00SF4355 3.90 2.10 0.51 0.34 0.36 0.09 0.03 0.02 0.00 0.00 0.00 DF95474.00 2.30 0.53 5.90 0.01 0.02 0.00 0.04 0.00 0.00 0.00 DF9179 4.20 2.400.52 0.48 0.48 0.01 0.00 0.01 0.00 0.00 0.00 DF9192 3.90 2.20 0.59 0.480.49 0.01 0.00 0.00 0.00 0.00 0.00 DF9232 4.00 2.10 0.63 0.38 0.43 0.010.00 0.00 0.00 0.00 0.00 DF9083 4.06 2.32 0.55 0.65 0.00 0.01 0.00 0.000.00 0.01 0.00 DF9518 3.80 2.20 0.58 0.00 0.54 0.01 0.00 0.00 0.00 0.000.00 DF9520 4.30 2.30 0.55 0.54 0.00 0.01 0.00 0.00 0.00 0.00 0.00DF9035 3.90 2.40 0.02 0.42 0.45 0.00 0.00 0.01 0.00 0.00 0.00 DF90823.85 0.04 0.47 0.00 2.57 0.01 0.00 0.01 0.00 0.02 0.00 DF9081 3.93 0.070.46 2.80 0.00 0.01 0.00 0.02 0.00 0.04 0.00 DF9545 4.30 2.30 0.59 0.540.00 0.47 0.00 0.00 0.00 0.00 0.00 DF9548 4.20 2.30 0.52 1.53 1.50 0.010.00 0.02 0.00 0.00 0.00 Tensile Properties Corrosion² 0.2% YS UTSElong. Chemical Analysis [wt %] [Mpy] [Mpa] [Mpa] [%] ID Al Fe Ni HRE¹Mpy Mpa Mpa % SF2894 0.007 0.003 0.001 0.46 40 n/m n/m n/m SF4619 0.010.002 0.001 0.67 43 209 298 19 SF4355 0.01 0.003 0.001 0.79 n/m 218 28619 DF9547 0.01 0.002 0.001 5.93 13 254 333 17.5 DF9179 0.01 0.002 0.0010.97 12 202 290 25 DF9192 0.01 0.002 0.001 0.98 9 208 286 28 DF9232 0.010.003 0.001 0.82 7 233 296 25 DF9083 0.006 0.002 0.001 0.66 10 193 28327 DF9518 0.01 0.002 0.001 0.55 8 204 279 25 DF9520 0.01 0.002 0.0010.55 8 212 292 24 DF9035 0.24 0.001 0.001 0.87 6 187 263 26 DF9082 0.0050.003 0.001 2.58 11 150 244 24 DF9081 0.008 0.003 0.001 2.81 11 152 25025 DF9545 0.01 0.002 0.001 1.01 8 198 286 26 DF9548 0.01 0.002 0.0013.04 12 223 307 24 ¹Sum of (only) Gd, Dy and Er

What is claimed is:
 1. A vascular implant made in total or in parts of abiodegradable magnesium alloy consisting essentially of: Y: 2.0-6.0% byweight, Nd: 1.5-4.5% by weight, Gd: 0-4.0% by weight, Dy: 0-4.0% byweight, Er: 0-4.0% by weight, Zr: 0.1-1.0% by weight, Li: 0-0.2% byweight, Al: 0-0.3% by weight; under the condition that: a) a totalcontent of Er, Gd and Dy is in the range of 0.82-4.0% by weight, and b)a total content of Nd, Er, Gd and Dy is in the range of 2.98-8.5% byweight; the balance being magnesium and incidental impurities up to atotal of 0.3% by weight.
 2. The vascular implant of claim 1, wherein thecontent of Y is 3.5-4.5% by weight.
 3. The vascular implant of claim 2,wherein the content of Y is 3.9-4.1% by weight.
 4. The vascular implantof claim 1, wherein the content of Nd is 1.5-3.0% by weight.
 5. Thevascular implant of claim 1, wherein the content of Nd is 2.0-3.0% byweight.
 6. The vascular implant of claim 1, wherein the content of Zr is0.1-0.7% by weight.
 7. The vascular implant of claim 1, wherein thetotal content of Er, Gd and Dy is in the range of 0.82-1.5% by weight.8. The vascular implant of claim 1, wherein the total content of Nd, Er,Gd and Dy is in the range of 2.98-3.5% by weight.
 9. The vascularimplant of claim 1, wherein the area percentage of particles in thealloy having an average particle size in the range of 1 to 15 μm is lessthan 3%.
 10. The vascular implant of claim 1, wherein the implant is astent.
 11. A method of manufacturing a vascular implant, comprising:providing a biodegradable magnesium alloy consisting essentially of: Y:2.0-6.0% by weight, Nd: 1.5-4.5% by weight, Gd: 0-4.0% by weight, Dy:0-4.0% by weight, Er: 0-4.0% by weight, Zr: 0.1-1.0% by weight, Li:0-0.2% by weight, Al: 0-0.3% by weight; under the condition that: a) atotal content of Er, Gd and Dy is in the range of 0.82-4.0% by weight,and b) a total content of Nd, Er, Gd and Dy is in the range of 2.98-8.5%by weight; the balance being magnesium and incidental impurities; andforming an implant up to a total of 0.3% by weight of the alloy.
 12. Themethod of claim 11, wherein the vascular implant is a stent.